17beta-hydroxy-17alpha-methylandrostane-3, 11-dione



17p-HYDROXY-17a-METHYLANDROSTANE-3, 11-11mm:

Milton E. Herr, Kalamazoo, Mich., assignor to The Upjohn Company,Kalamazoo, Micl x a corporation of Michigan No Drawing. ApplicationDecember 5, 1955 Serial No. 550,843

1 Claim. '(Cl. 260-4397.)

This invention pertains to organic compounds of the androstane seriesand is more particularly concerned with OH ca, 0. Q R

wherein R is selected from hydrogen and methyl. It is to be understoodthat the configuration of the S-hydrogen atom can be a or ,6 and thatboth forms are included within the scope of the present invention. Thedesignation Six-androstane is intended to represent androstane, and thedesignation S S-androstane is intended also to represent etiocholane.

It is an object of this invention to provide the 173-hydroxy-l7a-methylandrostane-3Jl-diones of the above formula. Saidcompounds are potent anabolic and androgenic agents having a favorableratio of anabolic to androgenic activity for anabolic agent purposes andcan be used in place of prior anabolic and androgenic agents in knownanabolic and androgenic pharmaceutical preparations. The compounds alsoare anti-pituitary agents and can be employed in place of knownanti-pituitary agents in pharmaceutical formulations used for thispurpose. Other objects and uses will be apparent to one skilled in theart.

The 17,8-hydroxy-l7m-methylandrostane-3Jl-diones of the above formulaare also useful in the form of their l7-monoacylate. Their acylate,e.g., acetate, propionate, trimethylacetate, on orfi-cyclopentylpropionate, a or ,8- cyclohexylpropionate, benzoate,phenylacetate, cyclohexylacetate, or or p-phenylpropionate, or otherhydrocarbon carboxylate, preferably containing from one to nine carbonatoms, inclusive, are useful for the same purposes as the parentcompounds, and in addition these esters are useful for the purificationof the parent 17,3- hydroxy-17a-methylandrostane-3,l l-diones.

The 17fi-hydroxy-l7a-methylandrostane-3,l l-diones of the presentinvention can be prepared readily from the corresponding 1 13,l7B-dihydroxy-l7oc-methylandrostane- 3-ones (starting compounds aredescribed in copending application Serial No. 550,845, filed December 5,1955, now US. Patent 2,842,570) by oxidation of the 11 8- hydroxy groupto an ll-keto group. The oxidation can be carried out using thepreferred chromic acid, potassium permanganate, potassium dichromate,N-bromoacetamide, N-chlorosuccinimide, tertiary-butyl hypochlorite, orother oxidizing agent, preferably using a solvent, e.g., acetic acid orchloroform with chromic acid, tertiarybutyl alcohol withN-bromoacetamide, N-chlorosuccinimide, or tertiary-.butyl hypochlorite,or other suitable solvent.

2,881,191 Patented Apr. '7, i959 The "17;? hydroxy 17ccalkylandrostane-3,'l ldiones and17B-hydroxy-l7ot-alkyl-19-norandrostane-3,1'ldiones wherein the alkylradical is preferably a loweralkyl radical containing from two to eightcarbon atoms, inclusive, e.g., .ethyl (particularly preferred), propyl,isopropyl, butyl, secondary-butyl, amyl, hexyl, heptyl, octyl, etc., areprepared by the same methods and have similar androgenic, anabolic, andanti-pituitary activity.

The following examples are illustrative of certain preferred productsand processes and are not to be construed as limiting the invention.

EXAMPLE 1 A solution of one gram of 113,17fl-dihydroxy-l7amethyl-5u-androstane-3-one in thirty milliliters ofglacial acetic acid ,is mixed with 0.8 gram of chromic anhydride (CrOdissolved in a mixture of three milliliters of water and thirtymilliliters of acetic acid. After the reaction mixture has stood forfive hours at room temperature, ten milliliters of methyl alcohol isadded, the mixture then concentrated in vacuo to small volume, and fiftymilliliters of water added. The solid which precipitates is recovered byfiltration, washed with water and dried in vacuo providing 0.687 gram ofl7fi-hydroxy-l7a-methyl- 5a-androstane-3,ll-dione melting at 190 to 215degrees centigrade with decomposition. Recrystallization from diluteaqueous acetone provides 0.427 gram of purified product melting at 210degrees centigrade with decomposition having [ot] equals plus 56 degreesin chloroform.

Analysis.--Ca1cd. fOI' C2DH3003I C, H, 9.50. Found: C, 74.93; H, 9.28.

EXAMPLE 2 l118,17 3-dihydroxy-l7a-rnethyl-5B-androstane-3-one isconverted by chromic acid oxidation to17/3-hYd1OXY-17umethyl-5fi-androstane-3,ll-dione, melting at 149-151degrees centigrade, following the procedure of Example 1.

EXAMPLE 3 Following the chromic acid oxidation procedure of Example 1 ll,8,l7B-dihydroxy-l7a-methyl-19-nor-5 aandrostane-3-one is converted tol7fl-hydroxy-l7wmethyll9-nor-5a-androstane-3,ll-dione and115,17B-dihydroxy- 17a-methyl-19-nor-5fl-androstane-3-one is convertedto 17,8-hydroxy-l7a-methyl-l9-nor-5 3-androstane-3,1l-dione. Other 175hydroxy l7a-alkyl-5u(and 5/3)-androstane 3,11-diones andl7fi-hydroxy-17a-alkyl-19-nor-5a(and 5fi)-androstane-3,ll-diones,wherein the alkyl radical is as defined and illustrated above, areprepared by the same procedure from corresponding11fi,17B-dihydroxy-17aalkyl-5a(and 5fi)-androstane-3-ones and1113,1713-dihydroxy-l7a-alkyl-19-nor-5a(and 5fi)-androstane-3-ones.

EXAMPLE 4 A solution of l-hydroxy-17tx-methyl-5a-androstane- 3,1l-dionein dry pyridine is heated under reflux with a oneto three-molar excessof acetic anhydride for about six hours. The mixture is then cooled,slowly diluted with water while stirring, and the solid precipitateobtained removed by filtration. The solid is washed with two percentaqueous hydrochloric acid solution and With water and then dried invacuo. Recrystallization or chromatographic separation provides purifiedl7p-hydroxyl7a-methyl-5a-androstane-3,ll-diones l7-acetate. In exactlythe same manner 17,8-hydroxy-l7a-methyl-5 8- androstane 3,11 dione 17acetate, 17B hydroxy-17a methyl l9 nor-5ot-androstane-3,1l-dionel7-acetate, and 17,8-hydroxy-17a-rnethyl-l9-nor-5li-androstane-3,ll-dione l7-acetate are prepared from 17/3-hydroxy-17a-methyl- 5Bandrostane 3,1l-dione, 17,8-hydroxy-l7a-methyl-19- nor 5ozandrostane-3,11-dione, andl7B-hydroxy-l7amethyl-19-nor-513-androstane-3,1l-dione, respectively,and

acetic anhydride. agent, i.e., the appropriate acid, acid anhydride oracid chloride, for the acetic anhydride in the foregoing procedureprovides other 17-acylates or 1713-hydroxy-l7amethyl-5a(and5fl)androstane-3,ll-dione and 17fl-hydroxy 17oz methyl-19-nor-5a( and5p)-androstane-3,11- dione including the l7-formate, propionate,trimethylacetate, furoate, on or fl-cyclohexylpropionate, benzoate,phenylacetate, a or p-cyclopentylpropionate, a or B- phenylpropionate,methylbenzoate, a or B-furylacrylate, valerate, methacrylate, and thelike. The foregoing 17- acylates can also be prepared by oxidation,according to the procedures of Examples 1 to 3, of corresponding 17-acylates of 1113,1713-dihydroxy-l7a-methyl-5a(and 55)- androstane-3-one,and 11B,17fi-dihydroxy-17a-methyl-19- nor-5a(and 5fl)-androstane-3-one.The 17-acylates of other 1713-hydroxy-17a-alkyl-5a(and5;8)-androstane-3,l1- diones and l7B-hydroxy-17a-a1kyl-l9-nor-Sa(and 58)- androstane-3,l1-diones, wherein the alkyl and acylate radicals areas defined and illustrated above, also are prepared by the foregoingprocedures.

Substituting the appropriate acylating' References Cited in the file ofthis patent UNITED STATES PATENTS Murray et a1. Dec. 14, 1954

